10a-phenyl-7a,10a-dihydrofurano(2&#39;,3&#39;:4,5)thiazolo(2,3-c)(1,2,4)benzothiadiazin-9(8h)-one-5,5-dioxide and derivatives thereof

ABSTRACT

COMPOUNDS OF THE FORMULA:   1,2-(-O-CO-(CH2)M-),5,5-DI(O=),R,1,2-DIHYDROTHIAZOLO   (2,3-C)(1,2,4)BENZOTHIADIAZINE   WHEREIN R AND R1 ARE, INDEPENDENTLY, HYDROGEN, LOWER ALKYL, HALOGEN, NITRO, TRIFLUOROMETHYL, OR LOWER ALKOXY; AND M IS 1 OR 2; HAVE CNS DEPRESSANT ACTIVITY.

United States Patent @fiice Patented Sept. 24, 1974 wherein R is hydrogen, lower alkyl, halogen, nitro, tri- 3,838,119 fiuoromethyl, or lower alkoxy and m is 1 or 2; to give an IOa-PHENYL 7a,l0a DIHYDROFURANO[2',3':4,5]

nt in d' t d f F l THIAZOLO[2,3-c][1,2,4]BENZOTHIADIAZIN-9(8H)- 1 fir e compo a W ONE-5,5-DIOXIDE AND DERIVATIVES THEREOF Peter H. L. Wei, Springfield, and Stanley C. Bel, Penn N Valley, Pa., assignors to American Home Products TS CH (CHZ E Corporation, New York, N.Y. R N =0 0H0 No Drawing. Filed Mar. 30, 1973, Ser. No. 346,494 l Int. Cl. C07d 93/32 US. Cl. 260-243 R 2 Claims 10 0 Q ABSTRACT OF THE DISCLOSURE 1V Compounds of the formula wherein R and R have the above-defined meanings. The N S z)m intermediate IV is then cyclized to give the final product.

ably aqueous potassium hydroxide. The intermediate acid (IV) is obtained by acidification of the salt which is o -s The first reaction is carried out in aqueous alkali, preferinitially formed. The cyclization is effected by heating the R n 2 intermediate acid (IV) in acetic anhydride.

1 The starting materials employed in the aforedescribed method of preparation are either known compounds or can be prepared from known compounds by conventional wherein R and R are, independently, hydrogen, lower methodsalkyl, halogen, nitro, trifluoromethyl, or lower alkoxy; when the compounds of the mveflilon are employd and m is 1 or ha,e CNS depressant activity. pharmacologically, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determinied by the solubility The lnven'flon Sought to be Patented comprlses chemical 3 and chemical nature of the compound, chosen route of Compounds having the Structural formula: administration, and standard pharmaceutical practice. 0 N For example, they may be administered orally in the form (cm)... of tablets or capsules containing such excipients as starch, GT3 lactose, magnesium stearate, and so forth. They ma be 0 y l O administered orally in the form of solution or they may be injected parenterally, e.g. intramuscularly. For parenteral administration, they may be used in the form of a steril solution or suspensions containing other solutes, for

example, enough saline to glucose to make'the solution 40 isotonic.

The dosage of the present pharmacologically active agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally,

treatment is intiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally The compounds of Folmllla Where R and m are as be found that when the composition is administered hereinbefore defined, exert a depressant action on the orally, larger quantities f the active agent i b central nervous system as demonstrated by evaluation in i d to d c th same effect as a smaller uantity Standard Pharmacologic test proceduresgiven parenterally. In general, the compounds of this in- The compounds of Formula I are prepared in tWO st ps. vention are most desirably administered at a dosage level First. a compound of Formula II: that will generally afford effective results without causing any harmful or deleterious side effects.

wherein R and R are, independently, hydrogen, lower alkyl, halogen, nitro, trifluoromethyl, or lower alkoxy; and m is 1 or 2.

As used herein the term lower alkyl or lower alkoxy" means a substituent having an alkyl moiety of from one to four carbons. The term halogen means a chloro, bromo, or iodo substituent.

The manner and process for making and using the in- N vention are illustrated in the following examples, where R \HTSH all temperature are given in degrees Centigrade.

H EXAMPLE I s .z 3- (p-Chlorobenzoyl -3- 6-Chloro-4LI; 1,2,4-Benzothiadi- 0 azin-3-Ylthio)Propionic Acid 5,5-Dioxide To an aqueous solution of 7-chloro-2-mercapto-1,2,4- wherem R 18 a hydrogen, lower y halogen, it tnbenzothiadiazine 5,5-dioxide 5.3 g., 0.0216 In.) and fluoromethyl, or lower alkoxy; is treated with a com- 5 potassium hydroxide (3.8 g., 0.067 m.) is added 3-bromopound of Formula III: 3-(p-chlorobenzoyl)propionic acid (6.6 g., 0.0226 m.). The solution is stirred at room temperature for four hours and then allowed to stand overnight. After filtering, the

-doH-(CHi)m-CoH filtrate is acidified with a 6N hydrochloric acid solution.

The solid material is collected and dried. Weight 8.0 g.

R The crude material is dissolved in hot dimethoxyethane,

' m filtered and concentrated. The residue is treated with 3 benzene and collected to give the title compound, mp. 237-239".

A/zaIysis.Calculatcd for: C 7H12Cl2N2O5S Z C, 44.45; H, 2.63; C1, 15.44; N, 6.10; S, 13.96. Found: C, 44.44; H, 2.84; CI, 15.46; N, 6.25; S, 14.23.

The IR spectrum shows absorptions for NH at 3.1 CO H at 5.85,u, keto 5.95,u., SO N at 7.7,u and 83,44.

EXAMPLE II 2-Chloro-10a(p Chlorophenyl 7a,10a Dihydrofurano [2',3:4,5]Thiazolo[2,3 c] [1,2,4]Benzothiadiazin 9- (8g)-One-5,5-Dioxide IR (KBr): 'y-lactone, 5.5 aromatic, 6.25m SO N, 7.6 and 8.5 NMR (DMSO): 6 7.6 (m, 7, aromatic); 4.58 (t, l, J=8Hq, methine); 3.40 (m, 2, COCH C).

EXAMPLE III The CNS-depressant effects of the compounds of Formula I are elicited and demonstrated by the following test procedure:

A compound of Formula I is administered orally (P.O.) or intraperitoneally (I.P.) to each of three mice. The animals are observed for signs of CNS-depressant activity, such as decreased motor activity, sedation, ataxia,

loss or righting reflex, and decreased respiration. When tested as above-described 2-chloro-l0a-(p-chlorophenyl- 7a,10a dihydrofurano[2,3':4,5]thiazole[2,3 c] [1,2,4] benzothiadiazin-9(8 H )-0ne-5,5-dioxide showed decreased motor activity and decreased respiration at 127 mg./kg. (I.P.).

What is claimed is:

1. A compound of the formula:

(CH2)m wherein R and R are, independently, hydrogen, lower alkyl, halogen, nitro, trifluoromethyl, or lower alkoxy; m is 1 or 2.

2. The compound as defined in Claim 1 which is: 2 chloro 10a (p-chlorophenyl-7a,lOa-dihydrofurano- [2,3':4,5] thiazolo [2,3 0] [1,2,4] benzothiadiazin 9- (8I )-one-5,5-dioxide.

References Cited UNITED STATES PATENTS 3,755,312 8/1973 Anderson et al 260-243 JOHN M. FORD, Primary Examiner U.S. Cl. X.R. 424-246 

